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Multicenter phase II study of tivozanib (AV-951) and everolimus (RAD001) for patients with refractory, metastatic colorectal cancer Wolpin BM; Ng K; Zhu AX; Abrams T; Enzinger PC; McCleary NJ; Schrag D; Kwak EL; Allen JN; Bhargava P; Chan JA; Goessling W; Blaszkowsky LS; Supko JG; Elliot M; Sato K; Regan E; Meyerhardt JA; Fuchs CSOncologist 2013[]; 18 (4): 377-8BACKGROUND: Treatments that target the vascular endothelial growth factor (VEGF) pathway have efficacy in colorectal cancer. We evaluated tolerability and efficacy of tivozanib (an oral VEGF receptor-1, -2, -3 inhibitor) plus everolimus (an oral mammalian target of rapamycin inhibitor). METHODS: The phase Ib study followed a 3 + 3 dose-escalation design with three dose levels. The primary objective in the follow-on phase II study was improvement in 2-month progression-free survival (PFS) from 30% (historical benchmark) to 50% in patients with refractory, metastatic colorectal cancer. RESULTS: Dose-limiting toxicities in the phase Ib study were grade 3 fatigue and dehydration. Oral tivozanib (1 mg daily for 3 of 4 weeks) and oral everolimus (10 mg daily continuously) were advanced to a 40-patient phase II study. The most common grade 3-4 adverse events were thrombocytopenia and hypophosphatemia. The 2-month PFS rate was 50%, with 20 of 40 patients having stable disease (SD). Seven (18%) patients were treated for >/=6 months. Median PFS and overall survival (OS) times were 3.0 months (95% confidence interval [CI]: 1.9-3.6 months) and 5.6 months (95% CI: 4.4-10.6 months), respectively. Patients who developed grade 1+ hypertension had increased SD rates (65.2% vs. 29.4%) and longer OS times (10.6 vs. 3.7 months). CONCLUSIONS: The oral combination of tivozanib and everolimus was well tolerated, with stable disease achieved in 50% of patients with refractory, metastatic colorectal cancer.|Antineoplastic Combined Chemotherapy Protocols[MESH]|Colorectal Neoplasms/*drug therapy/genetics/pathology[MESH]|Disease-Free Survival[MESH]|Drug-Related Side Effects and Adverse Reactions[MESH]|Everolimus[MESH]|Humans[MESH]|Neoplasm Staging[MESH]|Phenylurea Compounds/*administration & dosage/adverse effects[MESH]|Quinolines/*administration & dosage/adverse effects[MESH]|Sirolimus/administration & dosage/adverse effects/*analogs & derivatives[MESH]|Treatment Outcome[MESH] |
